Neural diseases, where cell death or cellular degeneration of the cells consisting of the nervous system such as neurocytes or glia cells are involved, include cerebrovascular disorders including cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, multi-infarct dementia, Binswanger type leukoencephalopathy, and chronic subdural hematoma; autoimmune diseases including multiple sclerosis, Guillain-Barré syndrome, and collagen disease; neurodegenerative diseases including spinocerebellar degeneration, Shy-Drager syndrome, amyotrophic lateral sclerosis, Alzheimer disease, Pick disease, Huntington chorea, Parkinson disease, progressive supranuclear palsy, epilepsy, and Prion disease; dementia or dysbasia associated with aging, or traumatic injury of spinal chord or cerebral disorders due to traffic accident. Among most of these diseases is commonly observed decrease in motor function (dyskinesia).
Dyskinesia includes muscular disorders, neural disorders, and disorders in bones and joints. Among these, central neural disorders leading to dyskinesia is classified according to the regions suffered into cerebral (frontal lobe), cerebellar, vestibular (labyrinth), and spinal dyskinesia.
Cerebral dyskinesia is caused by disorder in cerebral cortex, especially the frontal lobe, and can be observed in case of cerebrovascular lesion, cerebral atrophy, trauma, tumor, Pick disease, and chronic subdural hematoma. It exhibits atactic abasia and decrease in mental function.
Cerebellar dyskinesia is a significant symptom associated with, for instance, cerebellar disorders such as cerebellar tumor, vascular disorders, degenerative disorders, cerebellar atrophy, or deformity. Lesions in the vermis induce trunk ataxia, exhibits astasia-abasia, and gluteus maximus gait, yields difficulty in maintaining posture and position with disorder in balance. On the other hand, disorders in the cerebellar hemisphere exhibit abnormality of tonus in limb muscles and decrease in myotony and are accompanied by maldispositional gait towards the affected lateral direction, incoordination, wrong indication in finger-finger test or finger-nose test, dysmetria, Holmes-Stewart phenomenon, as well as intention tremor and cerebellar speech (scanning, explosive).
Vestibular (labyrinth) ataxia is caused by vestibular malfunctions and most of its cause is supposed to be the presence of, or sequela from, otological disorders in the internal ear, including, for instance, Ménière disease, sudden deafness, disorders in the balance-related nerves due to drug poisoning such as streptomycin or kanamycin, trauma, syphilis, acoustic trauma hearing loss, otosclerosis, and otitis interna (and its sequela).
In case of spinal dyskinesia, also called ataxia of posterior funiculus, disorders in posterior column of spinal cord lead to disorders in bathyesthesia, i.e. positional sensibility, articular sensibility and sensibility of grasp, resulting in ataxia. It is markedly observed in Friedreich's ataxia, subacute combined degeneration of spinal cord, locomotor ataxia, and the like.
These neurodegenerative diseases with dyskinesia are deeply related with cell death or cell degeneration of the neurocytes in their pathological conditions. For example, in case of poly(glutamic acid) disease, observed in Huntington disease, spinocerebellar degeneration (Machado-Joseph disease, Friedreich's ataxia, etc.) or myotonic dystrophy, or Alzheimer disease, cell death or cell degeneration of the neurocytes due to intracellular accumulation of abnormal proteins is observed. For motor neuronal disorders, typically amyotrophic lateral sclerosis, its cause is thought to be cell death of the neurocytes due to generation of free radicals or excessive accumulation of glutamic acid, increase in intracellular calcium ion level, or generation of NO. In case of Parkinson disease, its principal cause is thought to be degeneration of dopaminergic neurocytes in the stratum compacta of substantia nigra.
As the aging process proceeds, man's physical function continually deteriorates. As a morphological basis of the aging process, organs exhibit atrophy (i.e. decrease in weight). For example, the proceedings of the aging process render the brain atrophic, in its extremity resulting in gait disability or dementia. From histopathological point of view, there are observed degeneration or drop-off of the neurocytes, senile plaques, or change in Alzheimer fibril. Cell death or cellular degeneration of the nervous system is supposed to be induced by oxidative stress such as free radicals or glycation. It is also reported that biochemical observation of the brain autopsy revealed decrease in neurotransmitters, especially disturbance of cholinergic neurons, but the cause still remains to be elucidated.
Even if under healthy conditions, a man can fall into gait disability through injury of the spinal cord or the brain by, for instance, traffic accident. When a strong external pressure is applied in case of accidents, dislocation fracture of the spinal column occurs to press the spinal cord or to cause fractural injury in the spinal cord, resulting in injury of the spinal cord. Other causes include radiation burn, incised wound, or stab wound. It can also occur in case where wound is unobservable in bone as is often seen in hyperextension injury of the cervical vertebrae in which detrition and pressure lesion of the spinal cord is observed with marked hemorrhage and edema in parenchyma of the spinal cord. Its clinical symptom includes incomplete or complete systemic paralysis.
Autoimmune diseases are also sometimes accompanied by dyskinesia. Immune system ordinarily acts as a protective mechanism of the living body against a substance foreign and harmful to the host that invades from the environment into the living body. However, the system may sometimes act unfavorably against the living body. When this results in pathological conditions, it is called autoimmune diseases. Diseases exhibiting dyskinesia due to the autoimmune reaction include, for example, myasthenia gravis, multiple sclerosis, and rheumatoid arthritis.
Among these, multiple sclerosis, a kind of demyelination diseases, is characterized by the presence of a variety of demyelination nests of various sizes dispersed within the white matter of the central nervous system with varied lesions of old and new. The lesions are preferentially observed in the white matter such as the periphery of the lateral ventricle, the optic nerve, the brain stem or the spinal cord. Histologically, it is a disease where oligodendrocytes, engaged in formation of medullary sheath, are injured and a large number of oligodendrocytes are observed to have undertaken apoptosis in the lesions. The demyelination nests exhibit at early stage inflammatory infiltration of the cells, which are subsequently consolidated upon replacement with glial fiber at chronic stage. Its clinical symptoms include a various combination of symptoms such as optic neuritis, multiple vision, ocular motor disturbance such as nystagmus, spastic paralysis, painful tonic seizure, Lhermitte syndrome, ataxia, mogilalia and vesicorectal disturbance, where remission is often observed.
In case of cerebrovascular disorders, ischemic conditions in the brain induced by various causes such as cerebral infarction or intracerebral hemorrhage bring about oxygen lack and nutritional disturbance to the cells and tissues in the ischemic region. The oxygen lack first provides with functional impairment via blockage of ATP production, then leads to degeneration, necrosis or atrophy. Specifically, decrease in oxygen and glucose provisions due to ischemia triggers generation of free radicals, excess accumulation of glutamic acid, increase in intracellular calcium ion level, and enhancement of NO production, eventually resulting in death of neurocytes. The ischemic disturbance depends on the duration of ischemia such that the longer the duration of ischemia is, the more exacerbated the reperfusion injury becomes. With these reasons, cell death or cellular degeneration of neurocytes can be the cause of dyskinesia.
As stated above, neurodegenerative diseases with dyskinesia exhibit cell death or cellular degeneration of neurocytes as a common pathology although they may include various diseases. Therefore, any substance that may inhibit or ameliorate cell death or cellular degeneration of neurocytes would be considered to be an effective medicament for treating neurodegenerative diseases, especially dyskinesia. At present, for ameliorating these symptoms, a variety of medical drugs have been proposed, including, for example, a substance that prevents or controls oxidative disturbance in oxidases in the living body such as superoxide dismutase, catalase, or glutathione peroxidase, as well as clinically used medicaments such as trimetazidine hydrochloride, a medicament for treating ischemic heart disease; sodium oxagrel, thromboxane synthetase inhibitor; ifenprodil tartrate, a medicament for improving cerebral circulation and metabolism; and nizofenone fumarate, a medicament for improving ischemic encephalopathy. However, these medicaments cannot entirely inhibit dyskinesia.
As such, little medicament is known for effectively ameliorating symptoms in dyskinesia associated with cell death or cellular degeneration of neurocytes and hence symptomatic treatment has principally been employed. Thus, for instance, a medicament for treating Parkinson disease is used for parkinsonism such as tremor in hands, or an autonomic drug for autonomic symptoms such as orthostatic hypotension. Accordingly, for ameliorating dyskinesia induced by cell death or cellular degeneration of neurocytes, a substance is desired that can inhibit cell death or cellular degeneration generated under disadvantageous conditions for the neurocytes, especially a substance that can elevate anti-oxidative capacity of the cells.
The explanation mentioned above is described by reference to “Why cells die due to ischemia” by Kunio Tagawa, Kyoritsu Publishers Co., Ltd.; “Handbook of stroke” by Keiji Sano, I.P.C.; “Current Diagnosis and Treatment”, CD-ROM, Igaku-Shoin Ltd.; “Grand Medical Dictionary”, CD-ROM, Nanzando Co., Ltd.; “Up-to-date Grand Medical Dicitionary”, CD-ROM, 2nd Ed., Ishiyaku Publishers, Inc.; and “Apoptosis and Diseases”, Ed. by Yoshikuni Mizuno, Iyaku (Medicine and Drug) Journal Co., Ltd.